Dipeptidyl peptidase IV is a membrane bound non-classical serine aminopeptidase which is located in a variety of tissues including, but not limited to, intestine, liver, lung, and kidney. This enzyme is also located on circulating T-lymphocytes wherein it is referred to as CD-26. Dipeptidyl peptidase IV is responsible for the metabolic cleavage of the endogenous peptides GLP-1(7-36) and glucagons in vivo and has demonstrated proteolytic activity against other peptides such as GHRH, NPY, GLP-2 and VIP in vitro.
GLP-1(7-36) is a 29 amino acid peptide derived from post-translational processing of proglucagon in the small intestine. This peptide has multiple actions in vivo. For example, GLP-1(7-36) stimulates insulin secretion and inhibits glucagon secretion. This peptide promotes satiety and slows gastric emptying. Exogenous administration of GLP-1(7-36) via continuous infusion has been shown to be efficacious in diabetic patients. However, the exogenous peptide is degraded too rapidly for continual therapeutic use.
Inhibitors of dipeptidyl peptidase IV have been developed to potentiate endogenous levels of GLP-1(7-36). U.S. Pat. No. 6,395,767 to Hamann et al. discloses cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV. Methods for chemically synthesizing these inhibitors are disclosed in U.S. Pat. No. 6,395,767 as well as in the literature. For example, see Sagnard et al. Tet-Lett. 1995 36:3148–3152; Tverezovsky et al. Tetrahedron 1997 53:14773–14792; and Hanessian et al. Bioorg. Med. Chem. Lett. 1998 8:2123–2128. A preferred inhibitor disclosed in U.S. Pat. No. 6,395,767 is (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-1-oxoethyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, as depicted in Formulae M (HCl salt) and M′ (free base),
and the corresponding monohydrate of (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxytricyclo[3.3.1.13,7]dec-1-yl)-1-oxoethyl]-2-azabicyclo-[3.1.0]hexane-3-carbonitrile (M″) (all of which are collectively referred to as saxaglipitin).
Methods adapted for preparing intermediates used in the production of this dipeptidyl peptidase IV inhibitor are disclosed in EP 0 808 824 A2. Also see, Imashiro and Kuroda Tetrahedron Letters 2001 42:1313–1315, Reetz et al. Chem. Int. Ed. Engl. 1979 18:72, Reetz and Heimbach Chem. Ber. 1983 116:3702–3707, Reetz et al. Chem. Ber. 1983 116:3708–3724.
U.S. application Ser. No. 10/716,012 filed Nov. 18, 2003 discloses a method for preparing a DPP4 inhibitor compound 4 which requires a dehydration of compound 1 using pyridine-trifluoroacetic anhydride to give a mixture of products having trifluoroacetate group protection on hydroxy and amine or both (Compounds 6 and 7) and undehydrated-O-trifluoroacetate compound 5 as minor component. The nitrites 6 and 7 of the combined mixture then undergoes a hydrolysis step to give compound 2. Compound 1 is also formed in this reaction from compound 5, leading to loss of yield. If compound 1 is present in higher amounts after hydrolysis it may be difficult to remove it during crystallization of compound 2. Compound 2 is then subjected to another chemical process to deprotect the N-Boc group to form compound 3. HCl which on basification forms compound 4.
The above is illustrated by the following reaction sequence:

As can be seen from the above reaction scheme, the amide 1 is converted to the HCl salt 3 employing a three-step process wherein (1) amide 1 is made to undergo dehydration to form the cyano compounds 6 and 7; (2) the cyano compounds 6 and 7 are hydrolyzed to the alcohol 2, which is deprotected to form the HCl salt 3.
Although the above three-step procedure for producing HCl salt 3 from amide 1 is adequate, any improvement in such procedure which involves direct conversion of amide 1 to the HCl salt 3 (without the hydrolysis step) would be a most welcome improvement.